The recent literature discloses a variety of hydroxy-bisphosphonic acids which are useful in the treatment and prevention of diseases involving bone resorption. Representative examples may be found in the following: U.S. Pat. No. 3,962,432; U.S. Pat. No. 4,054,598; U.S. Pat. No. 4,267,108; U.S. Pat. No. 4,327,039; U.S. Pat. No. 4,621,077; U.S. Pat. No. 4,746,654; and EPO Publication 0252504.
The preparation of bisphosphonic acids and halo-bisphosphonic acids is also well known in the art. Representative examples may be found in the above mentioned references which dislose the compounds as being useful for the treatment of disturbances of calcium or phosphate metabolism, in particular, as inhibitors of bone resorption.
The bisphosphonic acids mentioned in the above references suffer from the problem of low oral bioavailability and, in addition, may exhibit gastrointestinal side effects particularly with the large oral doses required to provide therapeutic efficacy (see Br. J. Cancer, 52, 556 (1988)).
The preparation of simple esters of bisphosphonic acids and hydroxy-bisphosphonic acids, such as methyl, ethyl, propyl, and the like, is known in the art (for example see U.S. Pat. No. 3,705,191, U.S. Pat. No. 4,309,364, U.S. Pat. No. 4,371,527, U.S. Pat. No. 4,732,998, U.S. Pat. No. 4,746,654, EPO Publication 0252504, and J. Med. Chem., 30, 1426, (1987)). However, these simple esters are not readily hydrolyzed in vivo and do not yield satisfactory blood levels of the corresponding bisphosphonic acids.
Acyloxymethyl esters of monophosphates and monophosphinates have been reported (see U.S. Pat. No. 4,337,201, Bioorganic Chem., 1984, 12, 118, J. Pharm. Sci., 1983, 72, 324). Also, U.S. Pat. No. 4,732,998, U.S. Pat. No. 4,870,063, and PCT Publication No. WO 86/00902 describe alkanoyloxymethyl esters of thiomorpholino, alkoxy and aryloxy substituted bisphosphonic acids. However, the preparation of acyloxymethyl esters of the more potent hydroxy-bisphosphonic acids has not been previously described. Nor has the art recognized that these compounds may overcome the problem of poor oral bioavailability associated with the hydroxy-bisphosphonic acids of the prior art.